Abstract: Familial adenomatous polyposis (FAP) is a chronic disease that predictably leads to colorectal cancer if left untreated. Clinical trials have shown that COXIBs (selective cyclooxygenase-2 inhibitors), a subclass of nonsteroidal anti-inflammatory drugs (NSAIDs) that were originally developed to treat arthritis, effectively reduce the incidence of colorectal cancer in FAP patients. However, this class of drugs cannot be used clinically to treat FAP due to their severe systemic side effects including unstable angina, myocardial infarction, and cardiac thrombus. Drug companies have had to withdraw the chemopreventive indication of approved COXIBs (i.e., celecoxib) from the market due to these serious side effects. In this application, we propose to develop recycled colon bioavailable (r-CB) drugs to localize the active COXIBs in the colon by targeting enterohepatic circulation (EHC) via structure modification, resulting in low systemic drug exposure and high colonic drug exposure, thereby reducing the systemic side effects without sacrificing their efficacy. In the preliminary study, we have synthesized a few compounds and identified one (GS1) that is a potent COX-2 inhibitor undergoing efficient EHC. Based on these findings, we hypothesize that COX-2 inhibitor GS1 can effectively prevent or slow down the process of colon carcinogenesis with low systemic exposure in animal models relevant to FAP. Our long-term goal is to develop highly active r-CB COXIBs for the prevention of colorectal cancer that have limited or no systemic side effects in FAP patients. To prove the feasibility of r-CB drugs, we will: (1) evaluate the chemopreventive efficacy and systemic exposure of GS1 using the Pirc rat model (Aim 1); and (2) identify the transporter(s) facilitating EHC and evaluate the impact of EHC on the drug distribution using cell culture and/or animal models (Aim 2). The successful completion of this project will allow us to demonstrate that r-CB drugs that are only bioavailable in the colon can be created. This would enable selective treatment or prevention of the colonic cancer without severe systemic side effects. In addition, this project will allow us to generate preliminary data for the preparation of an R01-level proposal. It is expected that the research community will use this approach to develop drugs for the treatment of other colonic diseases; especially those related to COX-2- mediated colon carcinogenesis.